Dopamine exerts its physiological actions in the periphery as well as in the central nervous system (CNS) by interacting with multiple dopaminergic receptors. Recently, molecular biological approaches have established that the effects of dopamine in the CNS are mediated by at least three different receptors, namely D.sub.1, D.sub.2 and D.sub.3. See A. Dearry et al., Nature 347, 72-76 (1990); Q.-Y. Zhou et al., Nature 347, 76-80 (1990); R. Sunahara et al., Nature 347, 80-83 (1990); F. Monsma et al., Proc. Natl. Acad. Sci. USA 87, 6723-6727 (1990); J. Bunzow et al., Nature 336, 783-787 (1988); B. Giros et al., Nature 342, 923-926 (1989); F. Monsma, et al., Nature 342, 926-929 (1989); P. Sokoloff et al., Nature 347, 146-151 (1990). The genes encoding these receptors are distinct but homologous and belong to the large family of receptors coupled to guanine nucleotide regulatory protein (G protein). See B. O'Dowd et al., Ann. Rev. Neurosci. 12, 67-83 (1989). One major feature of these receptors is that they contain seven putative membrane spanning domains in their structure.
The actions of dopamine were originally thought to be mediated by an interaction with two distinct receptor subtypes: D.sub.1 receptors which were coupled to the stimulation of adenylyl cyclase and D.sub.2 receptors which were either uncoupled or coupled to the inhibition of adenylyl cyclase See J. Kebabian and D. Calne, Nature 277, 93-96 (1979). More recently, it has become apparent that multiple D.sub.1 receptors may exist. See P. Andersen et al., Trends Pharmacol. Sci. 11, 231-236 (1990). For instance, it has been demonstrated that injection of rat striatal mRNA into Xenopus oocytes directs the expression of a D.sub.1 dopamine receptor coupled to activation of phospholipase C and this activation leads to inositol phosphate (IPs) accumulation in injected eggs. L. Mahan et al., Proc. Natl. Acad. Sci. USA 87, 2196-2200 (1990). Furthermore, dopamine does not stimulate adenylyl cyclase in the amygdala, a tissue known to contain specific binding sites for the radiolabeled D.sub.1 -selective antagonist SCH 23390. P. Andersen et al., supra. In the periphery, D.sub.1 receptors have been shown to stimulate adenylyl cyclase as well as phospholipase C. See E. Baldi et al., Eur. J. Pharmacol. 149, 351-356 (1988); C. Missale et al., J. Cardiovasc. Pharmacol. 11, 643-650 (1985); C. Felder et al., J. Pharmacol. Exp. Ther. 248, 171-175 (1989). Moreover, peripheral D.sub.1 receptors differ pharmacologically from their CNS counterparts. Using the cloned human D.sub.1 receptor as a probe, we have reported that multiple hybridizing bands on Southern blot analysis at low stringency could be observed. This finding is consistent with the presence of other closely related receptors. A. Dearry et al., supra.
In the patent literature, a cloned gene encoding a mammalian D.sub.2 -dopamine receptor is reported in O. Civelli et al., PCT Patent Application WO 90/05780. A cloned gene encoding a mammalian D.sub.1 -dopamine receptor is described in J. Bunzow et al., Pending U.S. patent application Ser. No. 07/583,852, filed Sep. 17, 1990. Insofar as these applicants are aware, no distinct subtypes of D.sub.1 -dopamine receptors have previously been disclosed.